The hypnotic bromovalerylurea ameliorates 6-hydroxydopamine-induced dopaminergic neuron loss while suppressing expression of interferon regulatory factors by microglia
| Autor: | Naoto Seo, Keisuke Miyamoto, Haruna Takeda, Chisato Kawamoto, Yurika Ishii, Hiromi Higaki, Hisaaki Takahashi, Mohammed E. Choudhury, Afsana Islam, Kazuya Miyanishi, Kana Sugimoto, Hajime Yano, Junya Tanaka |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty medicine.medical_treatment Gene Expression Substantia nigra Proinflammatory cytokine 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Internal medicine medicine Animals Hypnotics and Sedatives Rats Wistar Oxidopamine Cells Cultured Hydroxydopamine Dose-Response Relationship Drug Microglia Pars compacta business.industry Dopaminergic Neurons Growth factor Dopaminergic Cell Biology Coculture Techniques Rats 030104 developmental biology Endocrinology medicine.anatomical_structure Interferon Regulatory Factors Immunology Bromisovalum business 030217 neurology & neurosurgery Interferon regulatory factors |
| Zdroj: | Neurochemistry International. 99:158-168 |
| ISSN: | 0197-0186 |
| Popis: | The low molecular weight organic compound bromovalerylurea (BU) has long been used as a hypnotic/sedative. In the present study, we found that BU suppressed mRNA expression of proinflammatory factors and nitric oxide release in lipopolysaccharide (LPS)-treated rat primary microglial cell cultures. BU prevented neuronal degeneration in LPS-treated neuron-microglia cocultures. The anti-inflammatory effects of BU were as strong as those of a synthetic glucocorticoid, dexamethasone. A rat hemi-Parkinsonian model was prepared by injecting 6-hydroxydopamine into the right striatum. BU was orally administered to these rats for 7 days, which ameliorated the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and alleviated motor deficits. BU suppressed the expression of mRNAs for interferon regulatory factors (IRFs) 1, 7 and 8 in the right (lesioned) ventral midbrain as well as those for proinflammatory mediators. BU increased mRNA expression of various neuroprotective factors, including platelet-derived growth factor and hepatocyte growth factor, but it did not increase expression of alternative activation (M2) markers. In microglial culture, BU suppressed the LPS-induced increase in expression of IRFs 1 and 8, and it reduced LPS-induced phosphorylation of JAK1 and STATs 1 and 3. Knockdown of IRFs 1 and 8 suppressed LPS-induced NO release by microglial cells. These results suggest that suppression of microglial IRF expression by BU prevents neuronal cell death in the injured brain region, where microglial activation occurs. Because many Parkinsonian patients suffer from sleep disorders, BU administration before sleep may effectively ameliorate neurological symptoms and alleviate sleep dysfunction. |
| Databáze: | OpenAIRE |
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